NASHVILLE, Tenn.—Drug discovery
research is frequently
criticized for taking the well-traveled path—whether it's the penchant of the
U.S. National Institutes of Health (NIH) to fund conservatively couched grant
applications or Big Pharma
filing yet another New Drug Application for a
"me-too-but-a-little-better" therapeutic. The Vanderbilt Center for Neuroscience
Drug Discovery (VCNDD), however, is doing it differently.

"When we initiate a program," says the center's director,
Dr. P. Jeffrey Conn, "everything we do is
focused on high-risk endeavors that are not widely accepted
by the pharmaceutical industry. In each case, we build data sets and compounds
to de-risk
and build interest in a field that ultimately gains the interest of
pharma. This includes the companies that we partner with, as well as multiple
other
companies that initiate programs based on data that we publish and
present to validate these new efforts."

Vanderbilt University (VU) Medical
Center has been a leader
in drug discovery for more than 85 years, and was an early pioneer of the
cross-disciplinary translational approach to
medical research. The Vanderbilt
Program in Drug Discovery was created as a hybrid between academia and
pharmaceutical development, combining the
high-throughput screening strategies
of industry with the in-depth knowledge of basic biological research. The
success of this strategy, particularly
for the study of neurological disorders,
led to the creation of a dedicated VCNDD in early 2011.

The
VCNDD is focused on accelerating research that may lead
to new treatments for Parkinson's disease, Alzheimer's disease, schizophrenia
and other
disorders of the brain, combining pharmacology, molecular
pharmacology, medicinal chemistry, drug metabolism and pharmacokinetics as part
of a
multidisciplinary team. This setup broadly mimics the preclinical drug
discovery structure found in the pharmaceutical industry, but with greater
freedom to explore the higher-risk therapeutic targets commonly associated with
neurological disorders.

"A
key aspect of successful preclinical discovery programs pursuing drugs for
central nervous system (CNS) targets is the
efficient and accurate
identification of compounds that exhibit favorable blood-brain barrier (BBB)
permeation with little or no efflux transporter
liabilities, and whose unbound
concentrations in the brain freely and rapidly equilibrate with those in
plasma," states Dr. Thomas Bridges, a drug
discovery scientist in drug
metabolism and pharmacokinetics (DMPK) within the VCNDD and the Department of
Pharmacology at the VU Medical School. "To
that end, our approach provides
quantitative insight to compounds' brain distribution properties as a single,
largely species-independent variable
useful for establishing structure-activity
relationships (SAR), medicinal chemical optimization strategies and ultimately,
to aid clinical candidate
selection."

Dr. J. Scott Daniels, assistant professor of pharmacology
and director of DMPK at VCNDD,
explains: "When I arrived at Vanderbilt, I saw a
group of well-meaning, hard-working drug metabolism scientists struggling with
limited resources. The
pipetting systems we had in place weren't capable of the
throughputs and experimental integrity we needed, so we invested in a contemporary
liquid-
handling platform which met the requirements of our workflow."

With throughput a key consideration,
the VCNDD's Tecan unit
is equipped with three independent robotic arms—an eight-channel pipetting arm,
a 96-channel pipetting arm and a robotic
gripper arm—allowing parallel
processing of all three assays. Complete automation of these fundamental assays
is vital to streamline the DMPK group's
workflow, requiring integration of a
number of additional devices onto the deck of the instrument. These include
incubators, incubated shakers and a
microplate reader, providing
high-throughput, walkaway processing.

"The Freedom EVO 200 is a
workhorse for this type of work,
and some labs will be running 100-plus 96-well plates per day through the
system with very little, if any, human
intervention once the assay is set up,"
notes Kevin Moore, head of applications and solutions at Tecan. "The unit will
easily run up to 500 samples
per day in the three assays Vanderbilt is most
interested in. Often the system is set up during the day and then run from the
afternoon into the
evening unattended. Most customers like to run their system
daily to ensure a good return on investment. As an example, the setting up of
an IC50 plate
with compounds at different concentrations using the
eight-channel pipetting arm would take around 10 to 15 minutes per plate."

Daniels summarizes: "From struggling with single pipettors
on the bench, we have progressed to a fully automated linear
platform with
which we can perform several bread-and-butter assays every single week, driving
the drug discovery pipeline and taking risks in novel
targets in a way that
companies just cannot do given the current economic climate. By partnering with
an experienced laboratory automation equipment
manufacturer, we have been able
to make our facility into an efficient, high-throughput contemporary ADME
group."

What
progress has the VCNDD group reported to date? "To date, we have not had any
drug candidates in clinical trials,
" Conn admits. "However, we have
reached the stage of achieving preclinical candidate status for three programs,
each of which has been
partnered with a major company for further
development. While we cannot make firm predictions, if we are successful
in the preclinical development
stage for these efforts, we could be ready to
enter into Phase I clinical studies by the end of 2014.